Full Text PA-95-005 AIDS, DRUG ABUSE AND NEUROBIOLOGY NIH GUIDE, Volume 23, Number 40, November 18, 1994 PA NUMBER: PA-95-005 P.T. 34 Keywords: Drugs/Drug Abuse AIDS Neurological Disorders Biology, Molecular National Institute on Drug Abuse PURPOSE The Acquired Immunodeficiency Syndrome (AIDS) is particularly prominent in populations of drug abusers. The onset and spread of HIV infection and the development of AIDS in this population is only superficially understood. Associated with the AIDS epidemic is the re-emergence of tuberculosis (TB) and other diseases not early recognized as associated with AIDS. The reduction in the immunologic competence of the abuser by various drugs may be important in the selection and progression of particular diseases. Also, many drugs of abuse are themselves neurotoxic and may initiate or enhance the development of dementia relative to HIV and otherwise compromise the central nervous system. To enhance knowledge regarding drug modulation of the HIV infectivity and progression to AIDS, neuroscientists, endocrinologists, immunologists, chemists, molecular biologists and others are collectively invited to submit research and conference grant applications (singly or jointly) to bring about an understanding of how drug abuse affects HIV-related disease states. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This program announcement, AIDS, Drug Abuse, and Neurobiology, is related to the priority area of alcohol and other drugs. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0, or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit, public and private organizations, such as colleges, universities, hospitals, laboratories, units of State and local government, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards and program project (P01) grants. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISMS OF SUPPORT Support mechanisms include regular individual research project grants (R01), small grants (R03), conference grants (R13), FIRST awards (R29), Interactive Research Project Grants (IRPGs), and program projects (P01). Because the nature and scope of the research proposed in response to this program announcement may vary, it is likely that the size of an award will vary also. RESEARCH OBJECTIVES NIDA has comprehensive neuroscience and immunological research programs. This program announcement focusses on the interactions of these two broad areas and related problems of HIV infectivity, especially in the central nervous system (CNS), and complements other NIDA program announcements concerning drug abuse and AIDS. Basic Immunologic Research: Research covered in NIDA's previous AIDS announcement still of interest include: (a) basic understanding of direct and indirect drug actions on immune cells, including studies of unique drug receptors, (b) drug modulation of viral replication and ontogeny within the host and host cells, and (c) appropriate animal studies designed to understand disease onset and progression. Redefined and broadened areas of research are outlined below: AIDS Neurologic Manifestations: AIDS is frequently accompanied by neural degeneration that results in progressive cognitive, behavioral and motor deficits (known as the AIDS Dementia Complex (ADC)). Investigations focussed on understanding the disease have made several important findings. For example, it has been shown that the HIV coat protein modulates the NMDA (N-methyl-d-aspartate) type of excitatory amino acid receptor and psychomotor stimulants act on this receptor. This suggests that there might be important mechanisms in common between AIDS- and drug (of abuse) -induced neural damage. If this is the case, then there also may be common approaches to prevent or treat the neurotoxic process. Potential research areas include: o Mechanism of action of drugs of abuse (e.g., psychomotor stimulants, "designer drugs") on the progression of ADC using in vitro and in vivo models. o Nature of viral damage to specific functional brain regions or circuits especially relevant to drug abuse (e.g., mesocortical limbic system, hippocampus, cortical association areas, pyramidal and extrapyramidal motor areas, etc). o Mechanism of drug modified glutamate-induced neurotoxicity and AIDS-dementia-complex utilizing SAR approaches (e.g., study of NMDA antagonists, PCP, MK-801, and memantine); this includes the synthesis of new compounds. o Drug (of abuse) modulation of induction, propagation (e.g., across the blood-brain-barrier) and mechanism of drug modulation of HIV action (e.g, gp120 protein) in microglia (e.g., via cytokines) and their effects on neural cells. o Interrelationships of various drugs of abuse with non-neural cells (e.g., glia) to determine the basis for the onset and progression of specific complications, i.e., Kaposi's sarcoma, opportunistic infections, neurodegeneration. o Mechanism of neural degenerative diseases and other glial modulated changes exerted by release of cytokines; especially where opiates and other abused drugs may impact. o Multiple actions of drug (e.g., marijuana) use by AIDS patients in immune suppression and/or neurotoxic action, which may enhance the neurotoxicity of HIV. Neuronal Interactions with Other Systems (HPA, THYMUS): The transmission/progression of HIV is not only inhibited by the immune system, but also is dependent on several interacting systems primarily under CNS control. Mechanistic studies are needed to elucidate the mechanism of how drug-induced modulation of CNS control of susceptibility, disease onset and morbidity occurs, i.e., through direct action on the immune system, or indirectly via the neuroendocrine system (e.g., through interleukin release from the CNS or the hypothalamic-pituitary-adrenal axis (HPA) resulting in stimulation/depression of macrophages, lymphocytes). As opiates and other drugs inhibit neural and peripheral systems, studies should focus on understanding the mechanisms of such action on the onset and/or progression of the AIDS syndrome. Areas of research interest involve, but are not restricted to, studies of: o Central system's and corresponding peripheral receptors (e.g., in lymph, adrenals, pituitary) pertinent to these actions. o Nature and mechanisms of the inhibition of immunity by drugs of abuse, including accessory cell function with a focus on receptors on these peripheral cells. o Key role of interleukins (e.g., IL1, TNFa), other transmitters (e.g., NO) as primary intermediates involved in abused drug actions on the immune and nervous systems. o Significance and mechanism of opioid suppression of the immune system for pain therapy in AIDS patients; examine the potential of alternative analgesics (including acupuncture) which do not affect the immune system. The nervous system is linked to the immune system through noradrenergic, dopaminergic and peptidergic fibers innervating endocrine tissue via common chemical messengers and receptors. For example, interlukins inhibit the HPA-induced release of corticosterone, an action modulated by opioids through the central serotonergic system. Also, hypothalamic cytokine receptor(s) similar to lymphocytic receptors appear to mediate ACTH (and opiomelanocortin) secretion in response to IL1 via CRF activation. Other areas of investigation include: o Opioids (exogenous as well as endogenous) indirect actions on immunity as modulated by the neuroendocrine system. o Alteration by drugs of abuse on the feedback responses between the endocrine or immune systems and the CNS. o Role of stress in these actions. Several opioid systems have been identified in the immune cells. Of these the "Enkephalin-type" systems of lymphocytes have been identified as key intermediaries in their ability to kill viruses and modulate rejection during organ transplantation. Studies might examine: o Relationship and mechanism of immunomodulation by "enkephalin" and other systems of lymphocytes. o Synthesis of new delta antagonists/agonists to understand the mechanisms of, or to improve, their anti-viral action. Perinatal Issues: Abuse of illicit drugs during pregnancy impacts on the mother's health and the neural development of her fetus. The consequences of maternal substance abuse on the developing CNS, neuroendocrine and immune systems, pediatric HIV infection and infant's increased susceptibility to infections are important issues to be addressed and may include: o Effects of abused drugs on the mode of transmission of HIV prior to, during birth, or postnatally. o Role and status of these drugs on maternally-derived antibodies and other immune protection for the newborn. o In rodents and other animals, critical periods of development when drug activation of the immune system by viral antigens or certain cytokines profoundly affects the HPA. o Studies of the placenta, which has both neuroendocrine and immune functions, are important for understanding the development of the fetus, and could shed some light on the impact of drugs of abuse on the neonatal development, such as: o Abused drugs alteration of the distribution of neuropeptides, immune cell surface markers, cytokines, growth factors and receptors in normal human and animal (primate) placentas. Other Studies: Health seems to decline more rapidly and more severely in HIV-infected drug abusers than in other HIV subjects. Recent research has shown that morphine treatment (in monkeys) leads to the development of a new strain of HIV that is less responsive to treatment. This mutability has also been demonstrated in human populations. Studies might include: o Interaction of drugs of abuse with the HIV and the disease process related to mutant HIV strains. o HIV treatment drugs in appropriate model systems, their effect on immune capacity of drug abusers, especially for methadone and other drug treatment subjects. The pharmacokinetic parameters (absorption, distribution, metabolism and elimination) of drugs, virus and immune components transported across the blood-brain-barrier and placental barrier are important to understanding the onset and progression of HIV and the treatment of AIDS. Studies in this area may shed light on viral transmission to the CNS and to the fetus, including: o Drugs of abuse on the production of peptides (e.g., cytokines), other constituents and transport across these barriers. o Drugs (e.g., cocaine) influence on the transport, metabolism of AIDS treatment drugs (e.g., AZT) Behavior Studies: Behavioral approaches to study drug abuse and AIDS could range from preclinical studies such as the development of animal models to examine AIDS-related behaviors to the more clinical oriented formation and/or improvement of behavior modification techniques. Research issues might include: o Neural basis for risk taking: behavioral, neurobiologic, and cognitive mechanisms negatively predicting making decisions, e.g., trying cocaine, using unsterilized needles, having unprotected sex, other risks; single or multiple factor mechanisms related to inappropriate risks; gender factors. o Interventions for risk taking: e.g., apply attention deficit therapies (behavioral and pharmacological) to risk taking. o Influence of drugs of abuse on risk-taking behavior: e.g., measure if abused drugs, like alcohol, increase risk taking and impair judgment at doses much lower than those that affect coordination and speech. o Behavior modification techniques to reduce the liability of contracting AIDS, especially through drug self-administration. o Negative and positive reinforcement approaches to control this risk taking. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard AIDS-related application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301-710-0267. The title and number of this program announcement must be typed in Item 2a on the face page of the application. FIRST applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** The National Institute of Mental Health (NIMH) supports research directed at understanding the impact of HIV infection on the central nervous system, as well as research to develop effective strategies to prevent or reduce high risk behaviors that place individuals at risk for HIV infection. The NIMH is interested in receiving applications independent of this program announcement, which address these issues. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by an initial review group in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate national advisory council. Small grant (R03) applications do not receive a second level review by NIH staff. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the announcement. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; and o conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications recommended for further consideration assigned to the Institute. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or to answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Charles W. Sharp, Ph.D. Division of Basic Research National Institute on Drug Abuse Parklawn Building, Room 10A-31 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-1887 Email: csharp@aoada.ssw.dhhs.gov Direct inquiries regarding fiscal or grants management issues to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse Parklawn Building, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 Email: gfleming@aoada.ssw.dhhs.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under authorization of Section 301 of the Public Health Service Act (42 USC 241) and administered under PHS policies and Federal Regulations of Title 42 CFR 52, "Grants for Research Projects," Title 45 CFR Part 74 and 92, "Administration of Grants," and 45 CFR Part 46, "Protection of Human Subjects." Title 42 CFR Part 2, "Confidentiality of Alcohol and Drug Abuse Patient Records," may be applicable to these awards. Title 42 Part 241(d), "Certificates of Confidentiality and Communicable Disease Reporting," will also apply. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Sections of the Code of Federal Regulations are available in booklet form from the U.S. Government Printing Office. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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